title: Mutual inhibition between quinine and etoposide by human liver microsomes. Evidence for cytochrome P4503A4 involvement in their major metabolic pathways.
abstract: The mutual inhibition between quinine and etoposide with their major metabolic pathways (i.e. quinine 3-hydroxylation and etoposide 3'-demethylation) was examined in vitro by human liver microsomes. Etoposide inhibited quinine 3-hydroxylation in a concentration-dependent manner with a mean IC50 of 65 microM. The mean maximum inhibition by etoposide (100 micro) of quinine 3-hydroxylation was about 60%. Similarly, etoposide 3'-demethylation was inhibited by quinine in a concentration-related manner with a mean IC50 value of 90 microM. The mean maximum inhibition by quinine (100 M) of etoposide 3'-demethylation was about 52%. An excellent correlation (r = 0.947, p < 0.01) between quinine 3-hydroxylase and etoposide 3'-demethylase activities in six different human liver microsomes was observed. Two inhibitors of CYP3A4, ketoconazole (1 microM) and troleandomycin (100 microM), inhibited quinine 3-hydroxylation by about 90% and 80%, and etoposide 3'-demethylation by about 75% and 65%, respectively. We conclude that quinine and etoposide mutually inhibit the metabolism of each other, consistent with the previous finding that CYP3A4 catalyzes the metabolism of both substrates.
authors.affiliation: Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
authors.forename: X J
authors.initials: XJ
authors.lastname: Zhao
authors.forename: T
authors.initials: T
authors.lastname: Kawashiro
authors.forename: T
authors.initials: T
authors.lastname: Ishizaki
mesh_terms: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005047:Etoposide / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010090:Oxidoreductases, O-Demethylating / Q000037:antagonists & inhibitors; D011802:Quinidine / Q000031:analogs & derivatives / Q000378:metabolism; D011803:Quinine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: C013569:3-hydroxyquinidine; D005047:Etoposide; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; D010090:Oxidoreductases, O-Demethylating; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; D007654:Ketoconazole